Article

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo

Human Medical Genetics Program, School of Medicine, University of Colorado, P.O. Box 6511, Mailstop 8300, Aurora, CO 80045, USA.
New England Journal of Medicine (Impact Factor: 54.42). 05/2010; 362(18):1686-97. DOI: 10.1056/NEJMoa0908547
Source: PubMed

ABSTRACT Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.
To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.
We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.
We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

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    • "Data are shown for nine genotyped or imputed SNPs (Supplementary Table S1) whose effects could not be distinguished by logistic regression analysis, due to linkage disequilibrium (Supplementary Table S2), as well as for two additional potential functional SNPs, rs2236338 (Y247H) and rs2273844 (stop codon within 5' untranslated region). nt, nucleotide position on chromosome 14 (alleles denoted on forward strand); A1, effect allele (here, high-risk); A2, reference allele; A1 freq, A1 allele frequency in summary 7202 GV cases and controls; GWAS 1, data from 1388 GV cases and 2586 controls (Jin et al., 2010); GWAS2, data from 418 GV cases and 2810 controls (Jin et al., 2012); OR, odds ratio; CMH, Cochran-Mantel-Haenszel meta-analysis; L95, lower limit of 95% confidence interval; U95, upper limit of 95% confidence interval. Note that subject quality control was carried out using the combined GWAS1+GWAS2 dataset, and subjects in GWAS1 who were related to subjects in GWAS2 (pi-hat > 0.05; 4 GV cases, 43 controls) were removed. "
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    ABSTRACT: Generalized vitiligo (GV) is characterized by autoimmune destruction of melanocytes by skin-homing cytotoxic T-cells (CTLs) that target melanocyte autoantigens. Two recent genomewide association studies (GWAS) of GV in European-derived whites (EUR) have demonstrated genetic association with GZMB, encoding granzyme B, a marker of activated CTLs that mediates target-cell apoptosis, as well as autoantigen activation and consequent initiation and propagation of autoimmunity. Here, we describe detailed genetic analyses of the GZMB region of chromosome 14q12 to identify genetic variation potentially causal for GV, implicating two non-synonymous SNPs in strong linkage disequilibrium that comprise part of a common multi-variant high-risk haplotype, rs8192917-C- rs11539752-C (55R-94A). To identify possible uncommon deleterious variants that might "hitchhike" on the high-risk haplotype, we then carried out "next-generation" DNA re-sequencing of GZMB in 114 EUR GV patients. Overall, our findings support a direct causal role for the GZMB rs8192917-C-rs11539752-C haplotype (55R-94A) in the pathogenesis of GV.Journal of Investigative Dermatology accepted article preview online, 15 January 2013; doi:10.1038/jid.2013.5.
    Journal of Investigative Dermatology 01/2013; 133(6). DOI:10.1038/jid.2013.5 · 6.37 Impact Factor
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    • "Similarly, in the EUR population, vitiligo is also associated with multiple signals in the MHC class II region, at least one of which, between HLA-DRB1 and HLA-DQA1, appears to correspond to one in the Indian subcontinent population. However, in the EUR population vitiligo shows primary association with HLA-A in the distal class I region (Jin et al., 2010), specifically HLA-A*02:01 (Jin et al., 2012). In addition, studies in the Chinese population show principal MHC association in the class III region (Quan et al., 2010) and in the proximal class I region, between HLA-B and HLA-C (Liu et al., 2012). "
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    ABSTRACT: Generalized vitiligo is a disease in which patches of depigmented skin and overlying hair result from autoim-mune destruction of melanocytes in involved regions (Spritz, 2012). Clinic-based studies cite high prevalence of vitiligo in India, up to 8.8% (e.g., Handa and Kaur, 1999), although population-based surveys report much lower prevalence, 0.46% in Calcutta (Das et al., 1985) and 1.79% in South Gujarat (Mehta et al., 1973). Vitiligo is a distressing cosmetic pro-blem in individuals of dark skin photo-types, owing to striking contrast between lesions and unaffected skin. This may explain the reported high prevalence of vitiligo in India and the negative impact on perceived quality of life in this population (Parsad et al., 2003). Indeed, vitiligo has long been recognized in India (Singh et al., 1974), the specific use of UV light treatment was pioneered in India (Menon, 1945), and some of the earliest genetic studies of vitiligo were carried out there: of ABO blood groups, a1-antitrypsin, and haptoglobin, and subsequent candidate gene studies, including GCH1, ACE, CAT, CTLA4, GPX1, IL4, MBL2, and PTPN22, most yielding negative or conflicting results. Recently, Singh et al. (2012) tested the genetic asso-ciation of vitiligo in Indian patients with HLA-A, -B, -C in the major histocom-patibility complex (MHC) class I region and HLA-DRB1 in the class II region, identifying primary genetic association with HLA-DRB1*07:01. Here, we describe a more compre-hensive genetic association study of generalized vitiligo on the Indian sub-continent, using the Immunochip (Cortes and Brown, 2011) to screen 196,524 single-nucleotide polymorphisms (SNPs) in 128 loci previously implicated in autoimmune and inflammatory diseases, including 9,441 SNPs spanning the extended MHC on chromosome 6p. Our results suggest that there are at least two independent association signals in the MHC class II region, one located upstream of HLA-DRA and the other located between HLA-DRB1 and HLA-DQA1, generally similar to what we previously found in a genome-wide association study of vitiligo in European-derived whites (EUR) (Jin et al., 2010). Our initial study group consisted of 255 patients with generalized vitiligo and 377 unrelated non-vitiligo controls of Indian subcontinent (Pakistan, India, Sri Lanka, and Bangladesh) derivation. After quality control procedures, data for 120,724 remaining SNPs from 251 remaining cases were compared with those from 349 remaining controls. Sug-gestive association signals were consid-ered as clusters of nearby SNPs with trend P-values o10 À 5 . The Interna-tional Immunochip Consortium has agreed on a genome-wide significance criterion of Po5 Â 10 À 8 for studies utilizing the Immunochip (Cortes and Brown, 2011). As shown in Figure 1a and Supple-mentary Table S1 online, the only highly suggestive association signals were in the MHC class II gene region (Figure 1b), from rs3134942 (chr6:32168770) to rs2856674 (chr6:32659644), spanning the upstream part of NOTCH4 through HLA-DQB1. The principal region of association encompassed c6orf10--BTNL2–HLA-DRA–HLA-DRB5–HLA-DRB1–HLA-DQA1 (Figure 1b), with extensive linkage disequilibrium (LD) through this region in this population (Figure 1c). One SNP, rs482044, located toward the centromeric end of the region, between HLA-DRB1 and HLA-DQA1, achieved genome-wide significance (G allele; P ¼ 1.94 Â 10 À 8 , odds ratio (OR) ¼ 1.93; Table 1), remaining signifi-cant (P ¼ 4.86 Â 10 À 8) even after correction for the observed genomic inflation factor l ¼ 1.06. To determine which SNPs in the MHC class II region represent primary association with vitiligo versus are sig-nals secondary to LD, we applied a backward regression procedure, com-paring a model including the seven most significant MHC class II SNPs to alter-native models in which each SNP was removed one by one. This analysis suggested that this region contains two independent associated loci, one repre-sented by rs482044-G (located between HLA-DRB1 and HLA-DQA1) and the other represented by rs3129859-C (located 6680 nt upstream of HLA-DRA). Forward regression analysis of these two SNPs showed that the model composed of rs3129859 was signifi-cantly (P ¼ 4.4 Â 10 À 5) improved by adding rs482044, and that the model composed of rs482044 was significantly improved (P ¼ 6.0 Â 10 À 4) by adding rs3129859. In contrast to our previous findings in EUR (Jin et al., 2010), we observed no apparent association of vitiligo with SNPs in the MHC class I region in this Indian–Pakistani population (Figure 1a and b). Furthermore, considering loci represented on the Immunochip that have been reported to be associated with vitiligo in previous candidate gene studies from India, no SNPs in the ACE (3 SNPs), CTLA4 (505 SNPs), or IL4 (103 SNPs) gene regions showed even nom-inal association in the present study. To confirm the association of general-ized vitiligo with MHC class II region SNPs in the Indian subcontinent, we carried out a replication study of
    Journal of Investigative Dermatology 01/2013; May 2013(133):1369-1372. DOI:10.1038/jid.2012.501 · 6.37 Impact Factor
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    • "To date, a number of genetic susceptibility factors have been identified through linkage and association studies (Chen et al., 2005; Ren et al., 2009; Spritz, 2011); however, only a few genes/loci, such as NALP1 (Jin et al., 2007) and some HLA alleles (Zamani et al., 2001; Arcos-Burgos et al., 2002), have been consistently replicated in multiple studies. Notably, several recent genome-wide association studies (GWASs) of vitiligo in the Caucasian population have identified a number of susceptibility genes/loci (Jin et al., 2010a, 2010b, 2012), such as 1p13. "
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    ABSTRACT: To identify susceptibility loci for vitiligo, we extended our previous vitiligo genome-wide association study with a two-staged replication study that included 6,857 cases and 12,025 controls from the Chinese Han population. We identified three susceptibility loci, 12q13.2 (rs10876864, P(combined)=8.07 × 10(-12), odds ratio (OR)=1.18), 11q23.3 (rs638893, P(combined)=2.47 × 10(-9), OR=1.22), and 10q22.1 (rs1417210, P(combined)=1.83 × 10(-8), OR=0.88), and confirmed three previously reported loci for vitiligo, 3q28 (rs9851967, P(combined)=8.57 × 10(-8), OR=0.88), 10p15.1 (rs3134883, P(combined)=1.01 × 10(-5), OR=1.11), and 22q12.3 (rs2051582, P(combined)=2.12 × 10(-5), OR=1.14), in the Chinese Han population. The most significant single-nucleotide polymorphism in the 12q13.2 locus is located immediately upstream of the promoter region of PMEL, which encodes a major melanocyte antigen and has expression loss in the vitiligo lesional skin. In addition, both 12q13.2 and 11q23.3 loci identified in this study are also associated with other autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus. These findings provide indirect support that vitiligo pathogenesis involves a complex interplay between immune regulatory factors and melanocyte-specific factors. They also highlight similarities and differences in the genetic basis of vitiligo in Chinese and Caucasian populations.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.320.
    Journal of Investigative Dermatology 09/2012; 133(2). DOI:10.1038/jid.2012.320 · 6.37 Impact Factor
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